Kidney + Stem Cell Transplant for Immune Tolerance

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Stanford University

Disqualifiers: Cancer, HIV, Hepatitis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

15 Participants Needed

Trial Summary

What is the purpose of this trial?

The Stanford Medical Center Program in Multi-Organ Transplantation and the Division of Bone Marrow Transplantation are enrolling patients into a research study to determine if blood stem cells injected after kidney transplantation, in combination with lymphoid irradiation ,will change the immune system such that immunosuppressive drugs can be completely withdrawn. Patients must have a healthy, completely human leukocyte antigen (HLA)-matched brother or sister as the organ and stem cell donor. One to two months before kidney transplant surgery, blood stem cells will be removed from the donor and the cells will be frozen. After transplant surgery, the recipient will receive radiation and anti-T cell antibody treatments for two weeks to prepare for injection of the stem cells. The stem cells will be injected at the end of the two-week treatment. If the stem cells persist in the recipient, immunosuppressive drugs will be gradually reduced until they are withdrawn completely at least six months after transplantation. Patients will be followed in the Stanford clinics for transplant patients. Patients who live outside of the San Francisco Bay Area must remain near Stanford for six weeks after transplant surgery.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, it mentions that immunosuppressive drugs will be gradually reduced after the transplant, so you might need to adjust your medications during the study.

What data supports the effectiveness of the drug Treosulfan in the Kidney + Stem Cell Transplant for Immune Tolerance trial?

Research shows that Treosulfan, when used in combination with other treatments, can help create a stable immune environment that accepts donor cells without causing severe side effects. It has been effective in reducing toxicity and promoting successful engraftment in bone marrow transplants, making it a promising option for inducing immune tolerance. ^{1 2 3 4 5}

Is the Kidney + Stem Cell Transplant for Immune Tolerance treatment generally safe in humans?

Treosulfan, a key component of the treatment, has been shown to have a favorable safety profile with limited organ toxicity and minimal nonhematological side effects compared to other similar treatments. It has been used safely in various studies for conditions like ovarian cancer and hematopoietic stem cell transplantation, indicating it is generally safe for human use. ^{1 4 6 7 8}

How does the treatment Hematopoietic Cell Transplantation differ from other treatments for kidney transplant patients?

This treatment is unique because it combines kidney and stem cell transplants from the same donor to induce immune tolerance, potentially reducing the need for lifelong immunosuppressive drugs and preventing organ rejection. ^{9 10 11 12 13}

Research Team

Samuel Strober, MD

Principal Investigator

Stanford University

Eligibility Criteria

This trial is for kidney transplant patients at Stanford who have a healthy sibling with matching human leukocyte antigens (HLA). Participants must not have HIV, Hepatitis B or C, low white blood cell or platelet counts, high antibody levels against transplants, a history of cancer (except certain skin cancers), previous organ transplants, or allergies to rabbit proteins. They should agree to use reliable contraception for two years post-transplant.

Inclusion Criteria

I agree to use birth control for at least 24 months after my transplant.

I have a sibling who is a perfect match for a donation.

Kidney transplant performed at Stanford University Medical Center

Exclusion Criteria

I have been treated with rabbit ATG or am allergic to rabbit proteins.

Thrombocytopenia (platelet count less than 100,000/mm³)

My immune system is highly likely to reject a transplanted organ.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

4-8 weeks

Pre-Transplant Preparation

Blood stem cells are removed from the donor and frozen; recipients receive radiation and anti-T cell antibody treatments for two weeks

2 weeks

Transplantation and Initial Treatment

Kidney transplantation followed by injection of stem cells; patients receive mycophenolate mofetil for one month and cyclosporine for 6-12 months

6-12 months

Follow-up

Participants are monitored for graft function, chimerism, and immune tolerance; cyclosporine is tapered and potentially discontinued at 6 months

12 months

Treatment Details

Interventions

• Hematopoietic Cell Transplantation
• Total Lymphoid Irradiation

Trial Overview The study tests if injecting the patient with their HLA-matched sibling's blood stem cells after kidney transplantation and lymphoid irradiation can eliminate the need for lifelong immunosuppressive drugs. The process involves pre-transplant donor cell collection, post-surgery radiation and anti-T cell treatment before stem cell injection. If successful, drug withdrawal starts six months later.

Participant Groups

Group I: Immune tolerance, kidney transplantation Experimental Treatment 2 Interventions

Intervention: Participants will receive hematopoietic cell transplantation and Total lymphoid irradiation. The intervention is intended to induce immune tolerance in HLA-matched living donor kidney transplantation, to allow withdrawal of the immunosuppressive drugs. Immune tolerance is achieved through the development of donor/recipient mixed chimerism following combined kidney and hematopoietic stem cell transplantation from the living donor.

Hematopoietic Cell Transplantation is already approved in European Union for the following indications:

Approved in European Union as Trecondi for:

• Allogeneic haematopoietic stem cell transplantation for malignant and non-malignant diseases

Who Is Running the Clinical Trial?

Stanford University

Lead Sponsor

Trials

2,527

Recruited

17,430,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Findings from Research

A radiation-free conditioning regimen using Treosulfan successfully induced permanent mixed multilineage chimerism and donor-specific tolerance in recipient mice, demonstrating its potential for safer transplantation protocols.

Treosulfan showed lower nonhematological toxicity compared to traditional myeloablative treatments like irradiation or busulfan, making it a promising candidate for conditioning in organ transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Towards a myeloablative regimen with clinical potential: I. Treosulfan conditioning and bone marrow transplantation allow induction of donor-specific tolerance for skin grafts across full MHC barriers. van Pel, M., van Breugel, DW., Vos, W., et al.[2013]

Busulfan has a well-established role in high-dose chemotherapy for treating hematologic malignancies and has been extensively studied for over 30 years, providing a clear understanding of its efficacy and pharmacokinetics.

Treosulfan, a newer analogue of busulfan, shows promise in treating hematologic malignancies but requires further research to fully understand its complex metabolism and pharmacological activity, particularly its pharmacokinetics and pharmacodynamics in high-dose chemotherapy contexts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacology of dimethanesulfonate alkylating agents: busulfan and treosulfan. Galaup, A., Paci, A.[2013]

Treosulfan, an alkylating agent used for ovarian cancer, effectively depletes primitive hematopoietic stem cells in a dose-dependent manner, similar to busulfan, making it a potential alternative for conditioning before stem cell transplantation.

In a murine model, low-dose treosulfan combined with an immune-suppressive regimen allowed for stable mixed chimerism and donor-specific tolerance without causing graft-versus-host disease, suggesting its utility in nonmyeloablative transplantation protocols.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Addition of treosulfan to a nonmyeloablative conditioning regimen results in enhanced chimerism and immunologic tolerance in an experimental allogeneic bone marrow transplant model. Ploemacher, RE., Johnson, KW., Rombouts, EJ., et al.[2013]

Treosulfan, used in combination with fludarabine, shows a favorable toxicity profile and effective engraftment in allogeneic hematopoietic stem cell transplantation (SCT), with non-relapse mortality rates between 9-28%.

The regimen demonstrates low relapse rates (5-30%) and promising survival outcomes (40-80%), particularly in patients with myelodysplastic syndrome (36-70% survival) and leukemia in remission (60-70% survival), indicating its potential as a safer alternative to standard conditioning regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treosulfan-based conditioning before hematopoietic SCT: more than a BU look-alike. Danylesko, I., Shimoni, A., Nagler, A.[2013]

In a multicenter trial involving 56 patients with hematologic malignancies, treosulfan was safely administered as a conditioning agent for stem-cell transplantation, with no cases of engraftment failure and low nonrelapse mortality (20%) over 2 years.

The study found that treosulfan at a dose of 14 g/m² showed promising results, combining low toxicity with a lower incidence of relapse, making it a candidate for further research in conditioning regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allogeneic hematopoietic stem-cell transplantation in patients with hematologic malignancies after dose-escalated treosulfan/fludarabine conditioning. Casper, J., Wolff, D., Knauf, W., et al.[2019]

Treosulfan demonstrated significant antileukaemic activity in pediatric models of acute lymphoblastic leukaemia (ALL), achieving complete regression of tumors and long-term survival in treated mice, outperforming equitoxic doses of busulfan and cyclophosphamide.

While treosulfan caused some myelotoxicity and minor weight loss, these side effects were manageable, suggesting it could be a promising alternative conditioning agent for stem cell transplantation in patients with hematological malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antileukaemic activity of treosulfan in xenografted human acute lymphoblastic leukaemias (ALL). Fichtner, I., Becker, M., Baumgart, J.[2019]

In a study involving nine patients, the infusion of donor hematopoietic stem cells after kidney transplantation led to significant changes in protein profiles, suggesting a potential mechanism for inducing immune tolerance and preventing organ rejection.

The analysis revealed that proteins related to inflammation and the complement system were downregulated in patients receiving combined kidney and stem cell transplants, indicating a shift towards a more tolerant immune response compared to those with kidney transplants alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hematopoietic stem cell transplantation induces immunologic tolerance in renal transplant patients via modulation of inflammatory and repair processes. Wu, D., Qi, G., Wang, X., et al.[2021]

Injecting donor-derived CD34+ bone marrow stem cells into kidney transplant recipients can help induce tolerance, which is a key goal in transplantation.

In a clinical trial, the infusion of these cells was found to be safe and well tolerated, with no adverse effects reported, highlighting their potential for improving transplant outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Infusion of donor-derived hematopoietic stem cells in organ transplantation: clinical data. De Pauw, L., Toungouz, M., Goldman, M.[2004]

Tr1 cell-enriched lymphocytes can be generated from patients on dialysis awaiting kidney transplantation, but using total peripheral blood mononuclear cells (PBMCs) resulted in a low anergic phenotype, making them unsuitable for clinical use.

In contrast, using purified CD4(+) T cells from these patients produced a highly anergic donor-specific product, indicating that tailoring the generation protocol to the patients' immune profiles can enhance the efficacy of this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Generation of Donor-specific T Regulatory Type 1 Cells From Patients on Dialysis for Cell Therapy After Kidney Transplantation. Petrelli, A., Tresoldi, E., Mfarrej, BG., et al.[2015]

References

1. England pubmed.ncbi.nlm.nih.gov

Towards a myeloablative regimen with clinical potential: I. Treosulfan conditioning and bone marrow transplantation allow induction of donor-specific tolerance for skin grafts across full MHC barriers. [2013]

2. England pubmed.ncbi.nlm.nih.gov

Toward a myeloablative regimen with clinical potential: II. Treosulfan induces specific skin graft tolerance across haploidentical MHC barriers. [2017]

3. England pubmed.ncbi.nlm.nih.gov

Pharmacology of dimethanesulfonate alkylating agents: busulfan and treosulfan. [2013]

4. United States pubmed.ncbi.nlm.nih.gov

Addition of treosulfan to a nonmyeloablative conditioning regimen results in enhanced chimerism and immunologic tolerance in an experimental allogeneic bone marrow transplant model. [2013]

5. England pubmed.ncbi.nlm.nih.gov

Treosulfan-based conditioning before hematopoietic SCT: more than a BU look-alike. [2013]

6. Italy pubmed.ncbi.nlm.nih.gov

Treosulfan-Based Conditioning Regimen in Sibling and Alternative Donor Hematopoietic Stem Cell Transplantation for Children with Sickle Cell Disease. [2020]

7. United States pubmed.ncbi.nlm.nih.gov

Allogeneic hematopoietic stem-cell transplantation in patients with hematologic malignancies after dose-escalated treosulfan/fludarabine conditioning. [2019]

8. England pubmed.ncbi.nlm.nih.gov

Antileukaemic activity of treosulfan in xenografted human acute lymphoblastic leukaemias (ALL). [2019]

9. England pubmed.ncbi.nlm.nih.gov

Hematopoietic stem cell transplantation induces immunologic tolerance in renal transplant patients via modulation of inflammatory and repair processes. [2021]

10. United States pubmed.ncbi.nlm.nih.gov

Infusion of donor-derived hematopoietic stem cells in organ transplantation: clinical data. [2004]

11. United States pubmed.ncbi.nlm.nih.gov

Generation of Donor-specific T Regulatory Type 1 Cells From Patients on Dialysis for Cell Therapy After Kidney Transplantation. [2015]

12. United States pubmed.ncbi.nlm.nih.gov

Allograft and patient survival after sequential HSCT and kidney transplantation from the same donor-A multicenter analysis. [2023]

13. United States pubmed.ncbi.nlm.nih.gov

Combined Bone Marrow and Kidney Transplantation for the Induction of Specific Tolerance. [2022]